Insulin Pump Therapy vs Multiple Daily Insulin Injections for Glycemic Control in Children With Type 1 Diabetes: A Systematic Review and Meta-Analysis

Type 1 diabetes mellitus (T1DM), characterized by the autoimmune destruction of pancreatic beta cells and consequent insulin deficiency, leads to various complications. Management primarily focuses on optimal glycemic control through intensive insulin therapy, either via multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using insulin pumps, which offer flexibility and improved basal insulin delivery. Despite the benefits of insulin pumps, such as reduced hypoglycemia risk and better mealtime insulin management, they pose challenges such as complexity in site changes and potential ketoacidosis due to tubing issues. This systematic review adheres to PRISMA guidelines and compares CSII with MDI in children and adolescents with T1DM, concentrating on outcomes such as glycemic control measured with HbA1c and glucose levels. The review includes studies meeting stringent criteria, encompassing a broad range of methodologies and geographies. The findings of this meta-analysis indicate the differences in glycemic control with CSII compared to MDI. However, significant heterogeneity in results and methodological variations across studies necessitate cautious interpretation. The study underscores the potential of CSII in offering better control for some patients, supporting a more personalized approach to T1DM management. It highlights the need for further research to understand the long-term effects and to refine treatment protocols, considering the variations in healthcare systems, treatment approaches, and patient demographics globally.


Introduction And Background
Type 1 diabetes mellitus (T1DM) is a significant global health concern, affecting millions of children and adolescents.The International Diabetes Federation (IDF) estimates 1,211,900 cases globally in those under 20 years old [1].T1DM arises from the autoimmune destruction of pancreatic beta cells, eliminating insulin production and leading to hyperglycemia and various complications, such as diabetic ketoacidosis (DKA), cardiovascular disease (CVD), neuropathy, nephropathy, and retinopathy [2,3].The primary goal in T1DM management is optimal glycemic control to minimize complications and enhance quality of life.Standard care involves intensive insulin therapy, typically through multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using insulin pumps [4,5].
Insulin pumps, which deliver insulin through a catheter inserted into the skin, offer certain advantages, especially in pediatric cases.They allow for flexibility in meal timing, extended catheter use, and programmable basal insulin delivery.Some pumps integrate with continuous glucose monitors (CGM), forming an automated insulin delivery system that reduces hypoglycemia risk [6,7].Despite these benefits, insulin pumps pose challenges, such as the complexity of changing infusion sites and potential complications such as ketoacidosis due to tubing issues [8,9].The variety of insulin pumps, including tubed or tubeless, patch or pod, and closed-loop or open-loop systems, cater to different patient preferences.However, cost and insurance coverage issues can limit their accessibility compared to MDI.Insulin pump therapy often utilizes rapid-acting analogs for their quick onset and short duration [8,9].
Given the rising popularity of insulin pump therapy among young patients, there is an ongoing debate about its merits compared to MDI, particularly in terms of glycemic control, hypoglycemia, and cost-effectiveness.The limitations of glycated hemoglobin (HbA1c) as a sole measure of glucose control necessitate a

Search methods
To ensure the inclusion of only high-quality studies, stringent inclusion and exclusion criteria were established.The exclusion criteria were rigorously applied to maintain the quality and relevance of the studies analyzed.Excluded were studies that did not focus on glycemic control measured by hemoglobin HbA1c, reported on animal models, or lacked original data.Additionally, studies that were not available in full text or could not be obtained via interlibrary loans were also excluded.
The literature search was conducted across multiple databases: PubMed MEDLINE (Table 1), Cochrane (Table 2), Scopus (Table 3), and Web of Science (Table 4).The search strategy employed Medical Subject Headings (MESH) terms and free-text terms relevant to our research question.The article selection process was guided by a PRISMA flowchart [13].This meticulous approach enabled the creation of a homogeneous dataset, facilitating a more accurate and reliable analysis of the results.

Types of Study
For our research, we conducted a systematic review of relevant studies published from 1993 to 2023, available in English; we meticulously screened and analyzed randomized clinical trials (RCTs), cohort studies, and case-control trials.This systematic review included studies that met the inclusion criteria: RCTs, case-control studies, and cohort studies when reporting glycemic control when using insulin pump therapy versus multiple daily injections.We excluded case series, cross-sectional, dissertations, book chapters, protocol articles, reviews, news articles, conference abstracts, letters to the editor, editorials, and comment publications.Furthermore, we excluded studies that did not clearly describe their operationalizations, were duplicated, and could not obtain the necessary data or receive a response from the original author via email.

Types of Participants
This study has set specific participant selection criteria, including both genders.The focus was on glycemic control in children with T1DM, including articles that report glycemic control levels measured by HbA1c.The glycemic control must be achieved by comparing an insulin pump with multiple insulin injections.Exclusion criteria are adults (anyone over 18) and children with type 2 diabetes.The study aims to include a variety of participants to gain a better understanding of the intervention.

Types of Intervention
To be eligible for inclusion in this study, the selected research must report glycemic control with HbA1c when children with T1DM use insulin pumps versus when they use multiple insulin injections.The control group can receive one of the two interventions.Studies that do not report glycemic control were excluded.

Outcomes
The outcomes to be measured include studies that report relevant outcomes, specifically hemoglobin HbA1c, and exclude studies that do not report relevant outcomes related to glycemic control measured by HbA1c, continuous glucose monitor (CGM), or capillary glycemic levels.

Data Extraction and Selection of Studies
During the initial phase, titles and abstracts of studies were screened by two independent reviewers (RFGW, SZS) using the predetermined inclusion and exclusion criteria.Rayyan software (Rayyan Systems Inc., Cambridge, MA) was used to facilitate the extraction of relevant data and filter duplicates.Keywords highlighting terms related to the inclusion and exclusion criteria were utilized in Rayyan [15].Any disagreements regarding study inclusion were resolved through consensus and consultation with a third reviewer (ECM).
Following this, a detailed full-text analysis was performed, where two other reviewers (IDM, TJK) independently selected trials based on the same inclusion and exclusion criteria.Disagreements in this stage were similarly resolved through consensus and with the assistance of the third review author (ECM).

Data Evaluation: Assessment of Risk of Bias
Our evaluation followed the criteria outlined in the Cochrane Handbook.The Cochrane Risk of Bias 2.0 tool was applied for RCTs [16], while the Newcastle-Ottawa Scale (NOS) was used for case-control studies [17].Two independent reviewers assessed the risk of bias in each study, considering the specific criteria and guidelines of the respective tools.Discrepancies between reviewers were resolved through discussion with a third, blinded reviewer (ECM).According to the Cochrane Handbook for Systematic Reviews of Interventions and NOS guidelines, the methodological aspects of the trials and case-control studies were categorized as having a low, high, or unclear risk of bias.Details regarding any changes in the quality of evidence, either downgrading or upgrading, were transparently presented in the summary of findings table, along with explanations for each bias assessment.

Statistical Analysis
Meta-analysis was conducted using R (version 2023.09.1+494;R Development Core Team, Vienna, Austria) [18].Effect sizes were presented as mean differences with 95% confidence intervals (CI).A random-effects model was employed to account for the heterogeneity of the studies [19,20], with I2 values of ≥50% and ≥75%, indicating substantial and considerable heterogeneity, respectively [20].The study removal method was applied in sub-analyses to evaluate the influence of individual studies on the overall effect size [21,22], considering p-values < 0.05 as statistically significant.

Results
A comprehensive search across four databases yielded 5,011 potential articles.After removing three duplicates, 126 publications were initially selected for retrieval.Following the screening, 84 were excluded, leaving 46 publications for eligibility assessment.Ultimately, 23 studies met the criteria and were included in the final review, comprising a total of 3,512 participants.This process is summarized in Figure 1.

FIGURE 1: PRISMA flow chart
In assessing the risk of bias for the 11 studies included in our systematic review, we employed Cochrane's Risk of Bias 2.0 tool for RCTs [16].Our analysis, depicted in Figure 2, indicates that one article (9%) presented a high risk of bias.In contrast, six articles (55%) raised some concerns, and the remaining four (36%) were assessed as having a low risk of bias.This assessment revealed that most of our selected RCTs fell into the low-risk to some-concern categories, with only one article (9%) labeled as high risk in red.For the remaining publications, which included both prospective and retrospective studies, the NOS [17] was used to evaluate bias, as seen in Table 5.According to our assessment, eight (67%) of these studies were classified as good quality, while the remaining four (33%) were categorized as fair quality.

FIGURE 2: Risk of bias of randomized control trials with Risk of Bias 2.0 tool
Sources: [16,[23][24][25][26][27][28][29][30][31][32][33] Risk of bias in each article.Eleven articles were assessed: one showed a high risk of bias, six showed some concerns, and the remaining four showed a low risk of bias.The primary outcome of the studies selected for this systematic review was to compare insulin pump therapy (CSII) with MDI in managing T1DM in children and adolescents.This comparison focused specifically on glycemic control as measured by hemoglobin HbA1c.The studies encompassed a broad geographic range, including Poland, the United States, Israel, Italy, Germany, Turkey, Saudi Arabia, Finland, Sweden, the Netherlands, England, and Wales.

Author, Year
While results varied across the selected publications, the majority (61%) indicated improved glycemic control with CSII compared to MDI.However, the remaining 39% of the studies either found no clinical benefit or no significant difference between the two methods.It is crucial to note that current research has limitations in fully understanding the intricacies of this topic.Future research should explore varied treatment protocols and address potential biases to deepen our understanding.The findings from these studies are summarized in Table 6.

FIGURE 3: Forest plot of the meta-analysis
A) Forest plot detailing the mean difference and 95% confidence intervals (CI) for the effect on HbA1c of CSII against MDI.B) Forest plot detailing the mean difference and 95% confidence intervals (CI) for the effect on glucose levels of CSII against MDI.
For glucose level analysis, 89 CSII cases and 90 MDI controls were reported.The mean glucose level difference, favoring CSII, was not statistically significant at 0.11 (CI: -0.66 to 0.88).This analysis also indicated heterogeneity, with a tau² of 0.22 and an I² of 69.1% (95% CI: 0%-93%).The heterogeneity test yielded a Q value of 3.24 with 1 degree of freedom, with a p-value of 0.07, as depicted in Supplementary Figure 3B.

Publication Bias
The funnel plot for HbA1c showed visual asymmetry (Figure 4A), suggesting potential publication bias.However, Egger's linear regression test resulted in a non-significant p-value of 0.79.For glucose levels, the funnel plot appeared symmetric (Figure 4B), indicating less concern for publication bias in this outcome.

Sensitivity Analysis and Subgroup Analysis
Sensitivity analysis was conducted, including a leave-one-out analysis, a gosh plot with K-mean, Gaussian mixture model (GMN), and DBSC, and a model's analysis.Inference analysis for effect size and a Baujat plot were used to detect articles that may have disproportionately influenced the results.This analysis does not reveleaded influence by country, year, or risk of bias.

Post-Hoc Analysis
GOSH plot analysis with the three algorithms, k-means (Figure 5A), DBSCAN (Figure 5B), and the GMN (Figure 5C), identified the study "Babiker, 2022," "Ata, 2021," "Mueller, 2018" as contributing to the overall heterogeneity.Leave-one-out analysis of the meta-analysis about HbA1c is presented in Figure 5D.The plot indicated how the omission of each study influenced the overall effect size estimate.Meta-analysis about HbA1c with this article's omission results in changes to the effect size, confidence intervals, and funnel plots.The heterogeneity values notably reduced to an I² of 34%, but the standardized mean difference remained statistically non-significant at 0.06 (CI: -0.04 to 0.16) (Figure 6A).The funnel plot after articles omission is presented in Figure 6B.

Discussion
This systematic review and meta-analysis, which synthesizes data from 23 articles, aims to compare glycemic control in pediatric patients treated with CSII versus MDI.Our qualitative findings suggest that patients on CSII generally achieved better glycemic control than those on MDI.This was refuted by our quantitative analysis, which does not show a statistical difference between the protocols for glycemic control.
The relationship between insulin delivery methods (CSII or MDI) and glycemic control in children and adolescents with T1DM is complex.While a majority of the studies in the systematic review (61%) indicated improved glycemic control with CSII, the remaining 39% found no significant difference or clinical benefit compared to MDI, and the meta-analysis did not find a statistically significant difference between the two protocols.This variation underscores the importance of considering individual patient characteristics, preferences, economic status, and access when selecting a treatment protocol.The mean differences in HbA1c and glucose levels of CSII against MDI were not statistically significant.The observed heterogeneity in the analyses might be attributed to variations in study designs, patient populations, or other factors such as technology improvement of CSII devices, despite the fact we run a meta-regression for a year and did not find the year as a contributing factor of the heterogeneity, warranting a cautious interpretation of these findings.
Our systematic review contributes to the body of literature by including a broader range of studies compared to previous meta-analyses, thus offering a more comprehensive overview of CSII versus MDI in pediatric T1DM patients.Notably, recent meta-analyses suggested enhanced effectiveness of CSII, particularly when combined with DPP-4 inhibitors or GLP1 agonists [46], and a significant reduction in glucose variability compared to MDI [47].
This research is globally significant as it underscores the potential of CSII to offer better glycemic control for some individuals, potentially leading to improved treatment protocols and health outcomes.The results support a move towards more personalized medicine in T1DM treatment.However, the considerable heterogeneity and the lack of statistically significant differences between CSII and MDI highlight the need for further research with new and most advanced CSII devices.This could involve larger and longitudinal studies to better understand long-term effects and develop more effective treatment protocols.
The study's limitations, including potential publication bias and regional differences in treatment protocols, healthcare systems, and patient characteristics, should be addressed in future research.By conducting larger, more comprehensive studies and considering longitudinal impacts, we can continue to enhance our understanding of optimal treatment strategies for children and adolescents with T1DM.

FIGURE 4 :
FIGURE 4: Funnel plot detailing publication bias in the included studies in the meta-analysisA) Funnel plot detailing publication bias in the included studies in the meta-analysis of HbA1c.B) Funnel plot detailing publication bias in the included studies in the meta-analysis of glucose levels.

FIGURE 6 :
FIGURE 6: Post-hoc meta analysis of the included studies of HbA1cA) Post-hoc forest plot detailing the mean difference and 95% confidence intervals (CI) for the effect on HbA1c of CSII against MDI.B) Post-hoc funnel plot detailing publication bias in the included studies in the meta-analysis of HbA1c.

TABLE 5 : Newcasttle-Ottawa scale results per article [16]
Both CSII and MDI were equally effective, with similar metabolic control, frequency of hypoglycemia, and no difference in quality of life.